ENVIRONMENTAL TOXICOLOGY AND HUMAN HEALTH - Vol. I - Health Effects from Exposure to Chronic Levels of Industrial Chemicals - Y.

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1 HEALTH EFFECTS FROM EXPOSURE TO CHRONIC LEVELS OF INDUSTRIAL CHEMICALS Y. Takeuchi Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, Chiba, Japan Keywords: Chronic toxicity, Industrial chemicals, Specific toxicity, Neurotoxicity, Reproductive toxicity, Carcinogenicity, Immunotoxicity, n-hexane, 2-Bromopropane, Benzene, Extrapolation from animal data Contents 1. Definition of Chronic Toxicity 2. Specific Toxicity or Target Organs of Chemicals 2.1. Neurotoxicity 2.2. Reproductive Toxicity 2.3. Carcinogenicity of Chemicals 2.4. Immunotoxicity 3. Cases of Chronic Occupational Poisoning 3.1. Polyneuropathy Due to n-hexane 3.2. Reproductive Disorders Due to 2-Bromopropane 3.3. Leukemia Due to Benzene 4. Prevention 4.1. Hygienic Standard to Prevent Chronic Occupational Poisoning 4.2. Extrapolation from Data of Animal Experiment to Humans Glossary Bibliography Biographical Sketch Summary Chronic health effects on workers are usually caused by repeated exposure to industrial chemicals for a long time at rather low concentrations in the workplace. There is no clear definition about chronic occupational poisoning. Definition of chronic occupational toxicity is introduced from the viewpoint of the ACGIH (American Conference of Governmental Industrial Hygienists) and the JSOH (Japan Society For Occupational Health). Industrial chemicals have some specific or major toxicity with other minor toxicity. Important, specific, or major toxicity such as neurotoxicity, reproductive toxicity, carcinogenicity, and immunotoxicity of chemicals are described, and industrial chemicals classified by specific toxicity are listed in the tables. Cases of chronic occupational poisoning such as n-hexane polyneuropathy, reproductive disorders due to 2-bromopropane, and leukemia associated to benzene are described as examples to understand health effects from exposure to chronic levels of industrial chemicals. The hygienic standards for industrial chemicals and viewpoints of the ACGIH and JSOH are described. Finally, important issues in extrapolation from data of animal experiments to

2 humans are described. 1. Definition of Chronic Toxicity Chronic health effects on workers are usually caused by repeated exposure of industrial chemicals for a long time at rather low concentrations in the workplace. There is no clear definition about chronic poisoning in terms of exposure period. Usually, health effects of acute poisoning are considered due to less than 5 15 minutes exposure of high concentration such as irritation and narcosis, etc. Sub-chronic poisoning is a rather specific health disorder due to moderate levels of exposure for less than 3 6 months. Chronic poisoning is a health disorder due to low levels of exposure for more than 3 6 months, which sometimes include aftereffects of acute and sub-chronic poisoning, malignant tumors occurring many years after exposure, effects on the following generations, shortening of life span and etc. Generally speaking, chronic poisoning could cause less specific health disorders than a sub-chronic one. Ambient concentrations in the workplace usually fluctuate in a wide range during working hours, day-by-day, and year-by-year. Workers are working 6 8 hours a day, 5 6 days a week, for about years, from starting of work to retirement. Therefore, the health disorders caused by occupational exposure from 3 6 months to years could be regarded as chronic poisoning. However, accurate assessment of long-term exposure might be very difficult because sufficient data of exposure levels are not available in most cases. 2. Specific Toxicity or Target Organs of Chemicals Industrial chemicals have one or more specific or major toxicity with minor toxicity, respectively. Some organs are specifically susceptible to some chemicals. For example, carbon tetrachloride is specifically toxic to the liver, cadmium is toxic to the kidney, benzene is toxic to the haematopoietic organs, n-hexane is toxic to the peripheral nerve, 2-bromopropane is toxic to the reproductive organs, benzene is an agent linked to causes of leukemia, toluenediisocyanate (TDI) is an allergen to cause asthma, and so on. The specific or major toxicity is important to detect early signs of health disorders, and establish the threshold limit values of chemicals to prevent the occupational poisoning, because it is the most sensitive parameters for toxicity of chemicals. However, it should be noted that industrial chemicals have other toxicity apart from major toxicity. Important specific or major toxicity such as neurotoxicity, reproductive toxicity, carcinogenicity, and immunotoxicity of industrial chemicals are described in the following section, and industrial chemicals classified by specific or major toxicity are listed in the tables Neurotoxicity Neurotoxicity is any effects on the structure or function of the central and/or peripheral nervous system related to exposure of a chemical substance. Recently, neurotoxicity has become an important endpoint in hazard identification and assessing the risks of chemicals. The nervous system is of particular interest because mature neurons are generally incapable of regeneration. The disorders of the nervous system due to chronic exposure to industrial chemicals are usually very hard to recover, and sometimes tend to

3 become gradually more serious even after removal from the exposure. In addition, the normal cascade of brain development during fetal and newborn life may be exquisitely sensitive to disruption by chemicals, resulting in lasting and profound nervous system dysfunction. Human exposure to potential neurotoxic substances is increasing public concern. Main neurotoxic chemicals to which workers may be exposed in the workplace are listed in the table (see Table 1). Chemicals Chemicals Acrylamide Mercury, inorganic Alkanes Methyl alcohol Anesthetic gases, waste Carbaryl Carbon disulfide Carbon monoxide Carbon tetrachloride Chloroform Cresol Dinitro-o-cresol Ethylene dibromide Fluorocarbon polymers, decomposition products Formaldehyde Hydrogen cyanide and salts Hydrogen sulfide Ketones Lead, inorganic/organic Methyl parathion Methyl chloride Nitriles Parathian Petroleum solvents, refined Styrene 1, 1, 2, 2-Tetrachloroethane Tetrachloroethylene Thiols Toluene 1, 1, 1-Trichloroethane Tungsten and cemented tungsten products Xylene Zinc oxide Malathion Table 1. Chemicals producing neurotoxic effects at low concentrations Reproductive Toxicity Reproductive toxicity encompasses adverse health effects in the prospective mother, the father, the developing embryo, and infant. The most striking features of reproduction are the myriad of rapid multiplying cells in the ovary, testis, or tissues of the embryo, and such cells to various chemicals would be much more susceptible than would be anticipated to elicit toxicity in other cell systems at low concentration. In reproductive toxicology, it is insufficient to determine that the target site of the agent is the testis, the ovary, and the conception, etc. The various direct and indirect events occurring during

4 the reproductive development cycle, each of these being characterized by multiple components should be examined. Information about reproductive toxicity of industrial chemicals is very limited as yet. Main well-known reproductive toxicants in the workplace are listed in the table (see Table 2). Chemicals associated with male Chemicals associated with female Boron Aromatic hydrocarbons (e.g. toluene) Benzene 2-Bromopropane 2-Bromopropane Cadmium Cadmium Carbon disulfide Carbon monoxide Carbon tetrachloride Carbaryl Chlordecone Chloroprene Dibromochloropropane (DBCP) Dimethyl dichlorovinyl phosphate (DDVP) Epichlorohydrin Estrogens Ethylene oxide Ethylene dibromide (EDB) Ethylene glycol ethers Lead Manganese Carbon monoxide Carbon disulfide Cytostatic drugs Dibromochloropropane (DBCP) Ethylene glycol Ethylene oxide Halogenated anesthetic gases Lead Mercury Nitrous oxide Manganese Ozone Polybrominated biphenyls (PBBs) Polystyrene Polychlorinated biphenyls (PCBs) Polybrominated biphenyls (PBBs) Polychlorinated biphenyls (PCBs) Polyurethane Styrene Table 2. Chemicals associated with reproductive disorders Carcinogenicity of Chemicals Cancer ranks as the toxic effects of most concern to the public. Because of this, considerable effort and financial resources are spent annually to identify potential human carcinogens. ACGIH (American Conference of Governmental Industrial Hygienists) classifies occupational carcinogens into A1 to A5. A1 is a confirmed human carcinogen including 18 chemicals. A2 is a suspected human carcinogen including 25

5 chemicals. A3 is a confirmed animal carcinogen including 83 chemicals. A4 is not classifiable as a human carcinogen including 83 chemicals. A5 is not suspected as a human carcinogen including 2 chemicals. JSOH (Japan Society for Occupational Health) classifies occupational carcinogens into group 1, group 2A, Group 2B according to the criteria of International Agency for Research on Cancer (IARC). Group 1 includes 20 chemicals that are carcinogenic to humans. Group 2A includes 20 chemicals that are probably carcinogenic to humans having more sufficient evidence. Group 2 B includes 103 chemicals that are possibly carcinogenic to humans having less sufficient evidence. Industrial chemicals classified into Group 1 and Group 2A by JSOH are listed in the table (see Table 3). Group 1 (carcinogenic to humans) 4-Aminophenyl Arsenic and compounds Asbestos Benzene Benzidine Benzotrichloride Bis (chloromethyl) ether Cadmium and compounds Chromium (VI) compounds Coal-tar pitches Coal-tars Erionite Ethylene oxide Mineral oils (untreated and mildly treated) 2-Naphthylamine Nickel compounds (except Ni metal) Soots Group 2A (probably carcinogenic to humans) Acrylonitrile Acrylamide Benzo [a] pyrene Beryllium and compounds 1, 3-Butadiene Chloromethyl methyl ether (technical grade) Creosotes 3, 3'-Dichloro-4, 4'-diaminodiphenylmethane (MBOCA) Diethyl sulphate Dimethyl sulphate Dimethylcarbamoyl chloride Epichlorohydrin Formaldehyde Sulphur dichlordiethyl Talc containing asbestiform fibers Vinyl chloride Wood dust P-Chloro-o-toluidine and its strong acid salts Polychlorinated biphenyl (PCB) Silica (crystalline) Styrene oxide Tris phosphate (2, 3-dibromopropyl) Vinyl bromide Vinyl fluoride Table 3. Occupational carcinogens.

6 - - - TO ACCESS ALL THE 12 PAGES OF THIS CHAPTER, Visit: Bibliography ACGIH (1999). Threshold limit values for chemical substances and physical agents, Biological Exposure Indices Cincinnati: ACGIH. [This recommends threshold limits values of many chemicals in the workplace.] Ellenhorn M. J. (1997). Principles of poison management; the pregnant patient. Ellenhorn s Medical Toxicology 2nd Ed. pp Baltimore: Williams and Wilkins. [This presents reproductive toxicity of many chemicals and their classification based on human and animal evidence.] JSOH (1999). Recommendation of Occupational Exposure Limits ( ). Journal of Occupational Health 41, [This recommends occupational exposure limits of many chemicals in Japan.] Kaneko T., Wang P. T., and Sato A. (1997). Benzene-Associated Leukemia and its Risk Assessment. Journal of Occupational Health 39, [This presents a comprehensive risk-assessment of benzene exposure in the workplace.] Koh J. M., Kim C. H., Hong S. K., Lee K. U., Kim Y. T., Kim O. J., and Kim G. S. (1998). Primary Ovarian Failure Caused by a Solvent Containing 2-Bromopropane. European Journal of Endocrinology 138, [This presents 2 years follow-up study on the patients with amenorrea caused by 2- bromopropane exposures in Korea.] Schulze G. E. (1995). Neurotoxicity. CRC Handbook of Toxicology (eds. Derelanko M. D. and Hollinger M. A.) pp New York: CRC press. [This presents a comprehensive description on neurotoxicity of many chemicals.] Takeuchi Y., Ono Y., Hisanaga N., Kitoh J., and Sugiura Y. (1980). A Comparative Study on the Neurotoxicity of N-Pentane, N-Hexane, and N-Heptane in the Rat. British Journal of Industrial Medicine 37, [This presents specific neurotoxicity of n-hexane compared with n-pentane and heptane in rats.] Takeuchi Y., Ichihara G., and Shibata E. (1997a). Modification of Hexane Neurotoxicity by Other Organic Solvents, its Mechanism, and Risk Assessment. Advances in Occupational Medicine and Rehabilitation 3(3), [This presents dose-response relationship of n-hexane polyneuropathy occurred in vinyl sandal manufacturers in Japan.] Takeuchi Y., Ichihara G., and Kamijima M. (1997b). A Review on Toxicity of 2-Bromopropane: Mainly on its Reproductive Toxicity. Journal of Occupational Health 39, [This presents the reproductive toxicity of 2-bromopropane based on the cases of workers and the results of animal experiments.] Thomas P., and House R. V. (1995). Pre-clinical Immunotoxicity Assessment. CRC Handbook of Toxicology (eds. Derelanko M. D. and Hollinger M. A) pp New York: CRC press. [This presents immunotoxicity assessment of many chemicals.] Biographical Sketch Dr. Yasuhiro Takeuchi is Director of Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, Chiba, Japan. His main research fields are Occupational and Environmental Health, Organic solvent poisoning (n-hexane polyneuropathy, Toluene-induced CNS

7 impairment, Reproductive toxicity of bromopropanes, etc), Neurotoxicology of industrial chemicals, Reproductive toxicology of chemicals, Occupational contact dermatitis, and Occupational health problems in small enterprises.